This is a proposal on the relationship of the structure of the thyroid hormone receptor to its response to hormone binding. The nuclear receptors for a super family of eukaryotic transcription factors that regulate gene expression in response to specific small-molecule ligands. The family includes the receptors for thyroid hormones (TR's), glucocorticoids, androgens, estrogens, retinoids and vitamin D. Naturally-occurring mutations in these receptors can participate in the pathogenesis of several human diseases, including cancers, syndromes resembling hormone deficiency, and other diseases In the proposed studies, the applicant will use the thyroid hormone receptor a a model receptor in a structural study to reveal the atomic-level causes of dysfunction in activation and repression of transcription. X-ray crystallography will be used to determine the structures of various mutant TR ligand-binding domains (LBD) bound to agonist ligands. The mutant receptors are selectively defective in aspects of receptor function; therefore, study of the dysfunctional molecules should allow dissection of those components of the TR LBD structure responsible for the receptor transcriptional activities. Structural information from these studies can be correlated to receptor properties measured in the biochemical lab and in some cases to the clinical features of affected patients. In this way, the studies are expected to contribute towards a general understanding of ligand-activated regulation of gene expression, and its role in the mechanism of certain diseases.